Events in pathogenesis and immunity during primary varicella-zoster virus (VZV) infection were examined in 64 healthy subjects and 21 immunocompromised patients. Activation of the interferon system and activation of circulating T lymphocytes were early immune responses that occurred during the incubation period in some healthy subjects. Elevated levels of 2-5A synthetase in peripheral blood mononuclear cells and detection of serum alpha interferon (IFN-a) and gamma interferon (IFN-y) were present in the majority of healthy subjects who had acute primary VZV infection. Expression of HLA- DR antigen occurred on circulating T lymphocytes from subjects with acute VZV infection. The early production of VZV-specific IgG or IgM antibodies did not correlate with the severity of the clinical infection, but the detection of T lymphocyte proliferation to VZV antigen within three days after the appearance of the varicella exanthem was associated with milder illness. The mean VZV-specific lymphocyte transformation for subjects with <100 lesions/m2 was 7.5 ± 1043 SD compared with 1.4 ± 1, 85 SD for those with >400 lesions/m2 (P <.05). Only one (7.7%) of 13 immunocompromised patients had early VZV-specific lymphocyte transformation compared with 19 (42%) of 45 healthy subjects (P<.05). The rapid host response to primary VZV infection was associated with rapid termination of viremia in healthy subjects; VZV was isolated from only 11% of peripheral blood mononuclear cell samples cultured within 48 hr after the appearance of the exanthem.